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The Measure of Ovarian Symptoms and Treatment (MOST) concerns is a validated patient-reported symptom assessment tool for assessing symptom benefit and adverse effects of palliative chemotherapy in women with recurrent ovarian cancer (ROC). We aimed to examine (i) how symptoms within MOST symptom indexes track together (i.e. co-occur) and (ii) the association between MOST symptom indexes and key aspects of health-related quality of life (HRQL).A prospective cohort of women with ROC completed the MOST-T35, EORTC QLQ-C30 and EORTC QLQ-OV28 at baseline and before each cycle of chemotherapy. Analyses were conducted on baseline and end-of-treatment data. Exploratory factor analysis and hierarchical cluster analysis identified groups of co-occurring symptoms. Path models examined associations between MOST symptom indexes and HRQL.Data from 762 women at baseline and 681 at treatment-end who completed all 22 symptom-specific MOST items and at least one HRQL measure were analysed. Four symptom clusters emerged at baseline and treatment-end: abdominal symptoms, symptoms associated with peripheral neuropathy, nausea and vomiting, and psychological symptoms. Psychological symptoms (MOST-Psych) and symptoms due to disease (ovarian cancer) or treatment (MOST-DorT) were associated with poorer scores on QLQ-C30 and OV28 functioning domains and worse overall health at both time points.Four MOST symptom clusters were consistent across statistical methods and time points. These findings suggest that routine standardized assessment of psychological and physical symptoms in clinical practice with MOST plus appropriate symptom management referral pathways is an intervention for improving HRQL that warrants further research.

Objective The Gynecologic Cancer InterGroup (GCIG)-Symptom Benefit Study was designed to evaluate the effects of chemotherapy on symptoms and health-related quality of life (HRQL) in women having chemotherapy for platinum resistant/refractory recurrent ovarian cancer (PRR-ROC) and potentially platinum sensitive with >= 3 lines of chemotherapy (PPS-ROC >= 3). Methods Participants completed the Measure of Ovarian Cancer Symptoms and Treatment (MOST) and European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire QLQ-C30 questionnaires at baseline and every 3-4 weeks until progression. Participants were classified symptomatic if they rated >= 4 of 10 in at least one-third of symptoms in the MOST index. Improvement in MOST was defined as two consecutive scores of = 10 points above baseline in the QLQ-C30 summary score scale (range 0-100). Results Of 948 participants enrolled, 910 (96%) completed baseline questionnaires: 546 with PRR-ROC and 364 with PPS-ROC >= 3. The proportions of participants symptomatic at baseline as per MOST indexes were: abdominal 54%, psychological 53%, and disease- or treatment-related 35%. Improvement was reported in MOST indexes: abdominal 40%, psychological 35%, and disease- or treatment-related 38%. Median time to improvement in abdominal symptoms occurred earlier for PRR-ROC than for PPS-ROC >= 3 (4 vs 6 weeks, p=0.044); median duration of improvement was also similar (9.0 vs 11.7 weeks, p=0.65). Progression-free survival was longer among those with improvement in abdominal symptoms than in those without (median 7.2 vs 2.5 months, p= 3 (p=0.29), and 102/481 (21%) of those with abdominal symptoms at baseline. Conclusion Over 50% of participants reported abdominal and psychological symptoms at baseline. Of those, 40% reported an improvement within 2 months of starting chemotherapy. Approximately one in six participants reported an improvement in HRQL. Symptom monitoring and supportive care is important as chemotherapy palliated less than half of symptomatic participants. Funding Agencies|NHMRCNational Health and Medical Research Council of Australia [1063012, 570893]; Target Ovarian Cancer [UCL-P001AL]; Cancer Research UKCancer Research UK; UCL Cancer Trials Centre [C444/A15953]; Australian Government through Cancer AustraliaAustralian Government; NHMRC Program grantNational Health and Medical Research Council of Australia; Department of HealthEuropean Commission

BackgroundTetralogy of Fallot (TOF) is the most common cyanotic congenital heart disease encountered in pediatrics. Long-term survival after surgical repair has improved; however, reported mortality rates in unrepaired TOF are significant. Associated complications include neurological sequelae, most frequently brain abscess and stroke. In countries without early intervention for congenital heart disease including TOF, delayed presentations and complications require recognition by healthcare workers. Case presentationA 22 year old male with a history of unrepaired TOF presented to Rwanda’s tertiary university hospital, University Teaching Hospital of Kigali (CHUK) with acute right-sided hemiparesis. Diagnostic imaging identified a left-sided brain lesion consistent with brain abscess and cardiac mass concerning for an endocardial vegetation. He was managed with intravenous antibiotics, but subsequently died due to complications of septicemia. ConclusionIn countries where surgical repair of TOF is not available, early recognition and medical management are key in temporizing the development of devastating sequelae. Describing the prevalence of CHD in Rwanda is urgent, requiring further research by which effective prevention and treatment strategies can be developed.

We investigated the safety and efficacy of a combination of the oral tyrosine kinase inhibitor, nintedanib (BIBF 1120) with oral cyclophosphamide in patients with relapsed ovarian cancer.Patients with relapsed ovarian, fallopian tube or primary peritoneal cancer received oral cyclophosphamide (100 mg o.d.) and were randomised (1,1) to also have either oral nintedanib or placebo. The primary endpoint was overall survival (OS). Secondary endpoints included progression free survival (PFS), response rate, toxicity, and quality of life.117 patients were randomised, 3 did not start trial treatment, median age 64 years. Forty-five (39%) had received ≥5 lines chemotherapy. 30% had received prior bevacizumab. The median OS was 6.8 (nintedanib) versus 6.4 (placebo) months (hazard ratio 1.08; 95% confidence interval 0.72-1.62; P = 0.72). The 6-month PFS rate was 29.6% versus 22.8% (P = 0.57). Grade 3/4 adverse events occurred in 64% (nintedanib) versus 54% (placebo) of patients (P = 0.28); the most frequent G3/4 toxicities were lymphopenia (18.6% nintedanib versus 16.4% placebo), diarrhoea (13.6% versus 0%), neutropenia (11.9% versus 0%), fatigue (10.2% versus 9.1%), and vomiting (10.2% versus 7.3%). Patients who had received prior bevacizumab treatment had 52 days less time on treatment (P 0.01). 26 patients (23%) took oral cyclophosphamide for ≥6 months. There were no differences in quality of life between treatment arms.This is the largest reported cohort of patients with relapsed ovarian cancer treated with oral cyclophosphamide. Nintedanib did not improve outcomes when added to oral cyclophosphamide. Although not significant, more patients than expected remained on treatment for ≥6 months. This may reflect a higher proportion of patients with more indolent disease or the higher dose of cyclophosphamide used.Clinicaltrials.govNCT01610869.

Contains fulltext : 232064.pdf (Publisher’s version ) (Open Access) PURPOSE: The survival results of the PORTEC-3 trial showed a significant improvement in both overall and failure-free survival with chemoradiation therapy versus pelvic radiation therapy alone. The present analysis was performed to compare long-term adverse events (AE) and health-related quality of life (HRQOL). METHODS AND MATERIALS: In the study, 660 women with high-risk endometrial cancer were randomly assigned to receive chemoradiation therapy (2 concurrent cycles of cisplatin followed by 4 cycles of carboplatin/paclitaxel) or radiation therapy alone. Toxicity was graded using Common Terminology Criteria for Adverse Events, version 3.0. HRQOL was measured using EORTC QLQ-C30 and CX24/OV28 subscales and compared with normative data. An as-treated analysis was performed. RESULTS: Median follow-up was 74.6 months; 574 (87%) patients were evaluable for HRQOL. At 5 years, grade ≥2 AE were scored for 78 (38%) patients who had received chemoradiation therapy versus 46 (24%) who had received radiation therapy alone (P = .008). Grade 3 AE did not differ significantly between the groups (8% vs 5%, P = .18) at 5 years, and only one new late grade 4 toxicity had been reported. At 3 and 5 years, sensory neuropathy toxicity grade ≥2 persisted after chemoradiation therapy in 6% (vs 0% after radiation therapy, P < .001) and more patients reported significant tingling or numbness at HRQOL (27% vs 8%, P < .001 at 3 years; 24% vs 9%, P = .002 at 5 years). Up to 3 years, more patients who had chemoradiation therapy reported limb weakness (21% vs 5%, P < .001) and lower physical (79 vs 87, P < .001) and role functioning (78 vs 88, P < .001) scores. Both treatment groups reported similar long-term global health/quality of life scores, which were better than those of the normative population. CONCLUSIONS: This study shows a long-lasting, clinically relevant, negative impact of chemoradiation therapy on toxicity and HRQOL, most importantly persistent peripheral sensory neuropathy. Physical and role functioning impairments were seen until 3 years. These long-term data are essential for patient information and shared decision-making regarding adjuvant chemotherapy for high-risk endometrial cancer.

BackgroundTwo novel biological agents—cediranib targeting angiogenesis, and olaparib targeting DNA repair processes—have individually led to an improvement in ovarian cancer control. The aim of ICON9 is to investigate the combination of cediranib and olaparib maintenance in recurrent ovarian cancer following platinum-based therapy.Primary objectiveTo assess the efficacy of maintenance treatment with olaparib in combination with cediranib compared with olaparib alone following a response to platinum-based chemotherapy in women with platinum-sensitive ovarian, fallopian tube or peritoneal cancer during first relapse.Study hypothesisMaintenance therapy with cediranib and olaparib in combination is associated with improved patient outcomes compared with olaparib alone.Trial designInternational phase III randomized controlled trial. Following a response to platinum-based chemotherapy patients are randomized 1:1 to either oral olaparib and cediranib (intervention arm) or oral olaparib alone (control arm).Major inclusion criteriaPatients with a known diagnosis of high grade serous or endometrioid carcinoma of the ovary, fallopian tube or peritoneum, progressing more than 6 months after first-line platinum-based chemotherapy, who have responded to second-line platinum-based chemotherapy.Primary endpointsProgression-free and overall survival. Co-primary endpoints to be assessed using a fixed-sequence gatekeeping approach: (1) progression-free survival, all patients; (2) progression-free survival, BRCA wild type; (3) overall survival, all patients; (4) overall survival, BRCA wild type.Sample size618 patients will be recruited.Estimated dates for completing accrual and presenting resultsAccrual is expected to be completed in 2024 with presentation of results in 2025.Trial registrationClinicalTrials.gov: NCT03278717.

BACKGROUND:The PORTEC-3 trial investigated the benefit of combined adjuvant chemotherapy and radiotherapy versus pelvic radiotherapy alone for women with high-risk endometrial cancer. We updated the analysis to investigate patterns of recurrence and did a post-hoc survival analysis.METHODS:In the multicentre randomised phase 3 PORTEC-3 trial, women with high-risk endometrial cancer were eligible if they had International Federation of Gynaecology and Obstetrics (FIGO) 2009 stage I, endometrioid grade 3 cancer with deep myometrial invasion or lymphovascular space invasion, or both; stage II or III disease; or stage I-III disease with serous or clear cell histology; were aged 18 years and older; and had a WHO performance status of 0-2. Participants were randomly assigned (1:1) to receive radiotherapy alone (48·6 Gy in 1·8 Gy fractions given on 5 days per week) or chemoradiotherapy (two cycles of cisplatin 50 mg/m2 given intravenously during radiotherapy, followed by four cycles of carboplatin AUC5 and paclitaxel 175 mg/m2 given intravenously), by use of a biased coin minimisation procedure with stratification for participating centre, lymphadenectomy, stage, and histological type. The co-primary endpoints were overall survival and failure-free survival. Secondary endpoints of vaginal, pelvic, and distant recurrence were analysed according to the first site of recurrence. Survival endpoints were analysed by intention-to-treat, and adjusted for stratification factors. Competing risk methods were used for failure-free survival and recurrence. We did a post-hoc analysis to analyse patterns of recurrence with 1 additional year of follow-up. The study was closed on Dec 20, 2013; follow-up is ongoing. This study is registered with ISRCTN, number ISRCTN14387080, and ClinicalTrials.gov, number NCT00411138.FINDINGS:Between Nov 23, 2006, and Dec 20, 2013, 686 women were enrolled, of whom 660 were eligible and evaluable (330 in the chemoradiotherapy group, and 330 in the radiotherapy-alone group). At a median follow-up of 72·6 months (IQR 59·9-85·6), 5-year overall survival was 81·4% (95% CI 77·2-85·8) with chemoradiotherapy versus 76·1% (71·6-80·9) with radiotherapy alone (adjusted hazard ratio [HR] 0·70 [95% CI 0·51-0·97], p=0·034), and 5-year failure-free survival was 76·5% (95% CI 71·5-80·7) versus 69·1% (63·8-73·8; HR 0·70 [0·52-0·94], p=0·016). Distant metastases were the first site of recurrence in most patients with a relapse, occurring in 78 of 330 women (5-year probability 21·4%; 95% CI 17·3-26·3) in the chemoradiotherapy group versus 98 of 330 (5-year probability 29·1%; 24·4-34·3) in the radiotherapy-alone group (HR 0·74 [95% CI 0·55-0·99]; p=0·047). Isolated vaginal recurrence was the first site of recurrence in one patient (0·3%; 95% CI 0·0-2·1) in both groups (HR 0·99 [95% CI 0·06-15·90]; p=0·99), and isolated pelvic recurrence was the first site of recurrence in three women (0·9% [95% CI 0·3-2·8]) in the chemoradiotherapy group versus four (0·9% [95% CI 0·3-2·8]) in the radiotherapy-alone group (HR 0·75 [95% CI 0·17-3·33]; p=0·71). At 5 years, only one grade 4 adverse event (ileus or obstruction) was reported (in the chemoradiotherapy group). At 5 years, reported grade 3 adverse events did not differ significantly between the two groups, occurring in 16 (8%) of 201 women in the chemoradiotherapy group versus ten (5%) of 187 in the radiotherapy-alone group (p=0·24). The most common grade 3 adverse event was hypertension (in four [2%] women in both groups). At 5 years, grade 2 or worse adverse events were reported in 76 (38%) of 201 women in the chemoradiotherapy group versus 43 (23%) of 187 in the radiotherapy-alone group (p=0·002). Sensory neuropathy persisted more often after chemoradiotherapy than after radiotherapy alone, with 5-year rates of grade 2 or worse neuropathy of 6% (13 of 201 women) versus 0% (0 of 187). No treatment-related deaths were reported.INTERPRETATION:This updated analysis shows significantly improved overall survival and failure-free survival with chemoradiotherapy versus radiotherapy alone. This treatment schedule should be discussed and recommended, especially for women with stage III or serous cancers, or both, as part of shared decision making between doctors and patients. Follow-up is ongoing to evaluate long-term survival.FUNDING:Dutch Cancer Society, Cancer Research UK, National Health and Medical Research Council, Project Grant, Cancer Australia Grant, Italian Medicines Agency, and the Canadian Cancer Society Research Institute.

TPS5615Background: The benefit of lymphadenectomy on survival in stage 1 endometrial cancer remains uncertain. STATEC is a surgical trial designed to evaluate the use of nodal status after lymph no...

Epigenetics provides a molecular mechanism of inheritance that is not solely dependent on DNA sequence and that can account for non-Mendelian inheritance patterns. Epigenetic changes underlie many normal developmental processes, and can lead to disease development as well. While epigenetic effects have been studied in well-characterized rodent models, less research has been done using agriculturally important domestic animal species. This review will present the results of current epigenetic research using farm animal models (cattle, pigs, sheep and chickens). Much of the work has focused on the epigenetic effects that environmental exposures to toxicants, nutrients and infectious agents has on either the exposed animals themselves or on their direct offspring. Only one porcine study examined epigenetic transgenerational effects; namely the effect diet micronutrients fed to male pigs has on liver DNA methylation and muscle mass in grand-offspring (F2 generation). Healthy viable offspring are very important in the farm and husbandry industry and epigenetic differences can be associated with production traits. Therefore further epigenetic research into domestic animal health and how exposure to toxicants or nutritional changes affects future generations is imperative.

An ovarian follicle is composed of an oocyte and surrounding theca and granulosa cells. Oocytes are stored in an arrested state within primordial follicles until they are signaled to re-initiate development by undergoing primordial-to-primary follicle transition. Previous gene bionetwork analyses of primordial follicle development identified a number of critical cytokine signaling pathways and genes potentially involved in the process. In the current study, candidate regulatory genes and pathways from the gene network analyses were tested for their effects on the formation of primordial follicles (follicle assembly) and on primordial follicle transition using whole ovary organ culture experiments. Observations indicate that the tyrphostin inhibitor (E)-2-benzylidene-3-(cyclohexylamino)-2,3-dihydro-1H-inden-1-one increased follicle assembly significantly, supporting a role for the MAPK signaling pathway in follicle assembly. The cytokine interleukin 16 (IL16) promotes primordial-to-primary follicle transition as compared with the controls, where as Delta-like ligand 4 (DLL4) and WNT-3A treatments have no effect. Immunohistochemical experiments demonstrated the localization of both the cytokine IL16 and its receptor CD4 in the granulosa cells surrounding each oocyte within the ovarian follicle. The tyrphostin LDN193189 (LDN) is an inhibitor of the bone morphogenic protein receptor 1 within the TGFB signaling pathway and was found to promote the primordial-to-primary follicle transition. Observations support the importance of cytokines (i.e., IL16) and cytokine signaling pathways in the regulation of early follicle development. Insights into regulatory factors affecting early primordial follicle development are provided that may associate with ovarian disease and translate to improved therapy in the future.

LBA5503 Background: The aim of this 2 stage randomized trial was to evaluate whether women undergoing neoadjuvant IV chemotherapy followed by delayed debulking surgery benefit from the addition of IP/IV treatment after surgery. Methods: Stage 1 was a randomized 3-arm design including 2 IP platinum regimens: 153 women who received 3-4 courses of IV platinum-based chemo for stage IIB-III (IV pleural effusion only) EOC followed by optimal debulking surgery ( < 1 cm) were randomized to: ARM1 D1 IV paclitaxel (pacli) 135mg/m2 + IV Carboplatin AUC 5/6 with d8 pacli IV 60 mg/m2 Q 21d X3; ARM 2 D1 IV pacli 135mg/m2 + IP cisplatin (Cis) 75 mg/m2 and d8 IP pacli 60 mg/m2 Q21d X3; or ARM 3 d1 IV pacli 135mg/m2+ IP Carboplatin AUC 5/6 and d8 IP pacli 60mg/m2 Q21dX3. A planned DSMC review confirmed dropping ARM2 (IP cis) and continuing study as an expanded phase II comparing 200 patients randomized to ARMs 1 and 3, which has 80% power to detect a 19% difference in progression rate at 9 mo (PD9, primary endpoint), 2-sided α = 0.05. Progression free survival (PFS) and overall survival (OS) are secondary efficacy endpoints. Results: Between 2009 and May 2015, 275 patients were accrued: n = 101 Arm 1, 72 Arm 2, 102 Arm 3. Median age was 62; 81.8%s had stage 3 C disease; 12.7% stage IV. Baseline characteristics were balanced between arms. Median number of cycles was 3 all arms; completion rates Arm 1, 93.7% and Arm 3, 84.8%. Intention to treat PD9 rates: Arm 1: 38.6% (95% CI 29.1%- 48.8%) and Arm 3: 24.5% (95% CI 16.5%-34.0%); p = 0.065 stratified; p = 0.03 unstratified. Per protocol (eligible, received > one dose of protocol therapy) PD9 rates: Arm 1: 42.2% (95% CI 31.9%- 53.1%), Arm 3: 23.3% (95% CI 15.1%-33.4%); p = 0.03 stratified; p = 0.01 unstratified. Median PFS 11.3 mo (Arm1) and 12.5 mo (Arm 3); HR 0.82 (95% CI 0.57 - 1.17); p = 0.27. Median OS: 38.1 mo (Arm 1) and 59.3 mo (Arm 3); HR 0.80 (95% CI 0.47-1.35) p = 0.40. Adverse events > Gr 3 rates: 23% (Arm 1) and 16% (Arm 3) (p = 0.24). Conclusions: The IP carboplatin based regimen, post neoadjuvant chemotherapy and debulking surgery, is well tolerated and associated with a lower PD9 rate compared to IV therapy. Clinical trial information: NCT00993655.

5514 Background: Weekly paclitaxel (wPxl) has activity in platinum-resistant ovarian cancer (PROC). Upregulated Src kinase activity is seen in Pxl-resistant ovarian cancer models. This trial investigated the combination of wPxl and the oral Src inhibitor saracatinib (AZD0530) in PROC. Methods: Patients with PROC (defined as relapse within 6 months of prior platinum chemotherapy, confirmed either by CT scan or symptomatic CA125 rise) were randomised 2:1 to receive four 8 week cycles of wPxl (80mg/m2/week x6 with 2 week break) plus saracatinib (S; 175mg od) or placebo (P) continuously, starting 1 week prior to wPxl, until disease progression. Patients were stratified as 2 lines of prior chemotherapy; 78% (wPxL+S) vs 72% (wPxL+P) of patients received ≥1 cycle of wPxl; relative dose intensity was 96% vs 98% for wPxL+S and wPxL+P respectively. The 6-month PFS rate was 29% (wPxL+S) vs 35% (wPxL+P). Median PFS was 3.9 vs 5.3 months (HR 1.04; 95% CI 0.68, 1.59; p=0.86); median OS was 12.7 vs 12.8 months (HR 1.50, 95% CI 0.63, 3.56; p=0.36); RR were 0.0% vs 2.9% (CR) and 29% vs 38.9% (PR) for wPxL+S vs wPxL+P respectively. Median DoR was 5.6 vs 3.6 months; TTP was 3.9 vs 5.5 months (HR 1.10; 95% CI 0.71, 1.72;p=0.67). Grade 3+ Serious Adverse Events were 36.2% vs 30.6%; the most frequent toxicities (any grade) were abdominal pain (4.3%) and febrile neutropenia (4.3%) for wPxL+S, and vomiting (5.6%) for wPxL+P. Conclusions: In this randomised phase II trial, the addition of saracatinib to wPxl did not improve 6-month PFS in patients with PROC. Clinical trial information: NCT01196741.